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Tippani R.,Kakatiya University | Porika M.,Kakatiya University | Sirisha K.,Medicinal Chemistry Research Division | Abbagani S.,Kakatiya University | Thammidala C.,Kakatiya University
Current Pharmaceutical Biotechnology | Year: 2014

Pterostilbene is a naturally occurring dimethyl ether analog of resveratrol identified in several plant species. Telomerase is important in tumor initiation and cellular immortalization. Given the striking correlations between telomerase activity and proliferation capacity in tumor cells, telomerase had been considered as a potentially important molecular target in cancer therapeutics. Molecular docking studies were performed on pterostilbene with the crystal structure of telomerase (3DU6). Pterostilbene was evaluated for its in vitro cytotoxicity in breast (MCF7) and lung cancer (NCI H-460) cell lines, antimitotic activity in green grams and telomerase activity. Curcumin was used as a standard. Docking results indicated good interaction between pterostilbene and the active site of telomerase and the docked energy of pterostilbene was -7.10 kcal/mol. Pterostilbene showed strong inhibitory effect on in vitro telomerase activity and cell growth in both the cell lines tested in a dose dependent manner. Cancer cells treated with 80 μM pterostilbene exhibited significant telomerase inhibition, after 72 hours (MCF-7 and NCI H-460; 81.52% and 74.69% reduction, respectively, compared to control). The IC50 of pterostilbene for anti-proliferative activity in MCF7 and NCI H-460 cell lines were found to be 30.0 and 47.2 μM, respectively. The best antimitotic activity was obtained with 80 μM of pterostilbene (100% reduction in water imbibition). All the above results were comparable to that of curcumin. The drug-related properties of pterostilbene were calculated using Molinspiration, Osiris Property Explorer and ACD/Chemsketch softwares. Pterostilbene obeyed Lipinski's Rule of Five indicating its therapeutic potential in humans. It was found that the telomerase inhibitory activity exhibited by pterostilbene was dependent of the cell viability and has the potential to be a new drug candidate against breast and lung cancers. © 2013 Bentham Science Publishers.


PubMed | Jawaharlal Nehru Technological University Anantapur, IGBMC, Albert Ludwigs University of Freiburg, Birla Institute of Technology and Medicinal Chemistry Research Division
Type: | Journal: Bioorganic chemistry | Year: 2014

A series of hydroxamates (4a-4l) were prepared from p-aminobenzoic acid to inhibit HDAC8. The idea is to substitute rigid aromatic ring in place of less rigid piperazine ring of hydroxamates reported earlier by our group. It is expected to increase potency retaining the selectivity. Result obtained suggested that the modifications carried out retained the selectivity towards HDAC8 isoform and increasing the potency in very few cases. Increase in potency is also associated with variation in cap aryl region. Two compounds (4f &4l) were found to inhibit HDAC8 at concentrations (IC50) less than 20M.


Kusuma P.K.,Medicinal Chemistry Research Division | Vedula G.,Andhra University
Rasayan Journal of Chemistry | Year: 2015

In present research; we tried to confirm 2-phenyl Quinazolin-4(3H)-one derivatives, which are broadly reported in the literature as scavenging agent. The study was carried out on a selected set of 40 novel 2-phenyl quinazoline- 4(3H)-one and consequently docked them into Scavenger receptor class B Type- I (SRCB 1). The analogues 7a-7a8 and 7b1-7b8 were found to be more potent inhibitor as they exhibit drug like activity. The entire test Compounds which have highest ligand energy compared to the Standard compounds. Structure based drug designing of these analogues may found a novel antioxidant for future study. © 2015, Rasayan Journal of Chemistry, c/o Dr. Pratima Sharma. All rights reserved.


Kowshik J.,Annamalai University | Baba A.B.,Annamalai University | Giri H.,Indian Institute of Technology Madras | Reddy G.D.,Medicinal Chemistry Research Division | And 2 more authors.
PLoS ONE | Year: 2014

Identifying agents that inhibit STAT-3, a cytosolic transcription factor involved in the activation of various genes implicated in tumour progression is a promising strategy for cancer chemoprevention. In the present study, we investigated the effect of dietary astaxanthin on JAK-2/STAT-3 signaling in the 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch (HBP) carcinogenesis model by examining the mRNA and protein expression of JAK/STAT-3 and its target genes. Quantitative RT-PCR, immunoblotting and immunohistochemical analyses revealed that astaxanthin supplementation inhibits key events in JAK/STAT signaling especially STAT-3 phosphorylation and subsequent nuclear translocation of STAT- 3. Furthermore, astaxanthin downregulated the expression of STAT-3 target genes involved in cell proliferation, invasion and angiogenesis, and reduced microvascular density, thereby preventing tumour progression. Molecular docking analysis confirmed inhibitory effects of astaxanthin on STAT signaling and angiogenesis. Cell culture experiments with the endothelial cell line ECV304 substantiated the role of astaxanthin in suppressing angiogenesis. Taken together, our data provide substantial evidence that dietary astaxanthin prevents the development and progression of HBP carcinomas through the inhibition of JAK-2/STAT-3 signaling and its downstream events. Thus, astaxanthin that functions as a potent inhibitor of tumour development and progression by targeting JAK/STAT signaling may be an ideal candidate for cancer chemoprevention. © 2014 Kowshik et al.


Purohit M.,JSS University | Mayur Y.C.,Medicinal Chemistry Research Division | Mayur Y.C.,Center for Drug Design
Medicinal Chemistry Research | Year: 2012

Synthesis and evaluation of cytotoxicity and anti-microbial activity of a series of 1,4-bis(4-substituted- 5-mercapto-1,2,4-triazol-3-yl)butane derivatives comprising thioether functionality and other pharmacophore modifications are described. All the newly synthesized compounds were characterized by IR, NMR, elemental analyses, and mass spectral studies. The compounds 4a-f, 5a-f, and 6a-f were evaluated for in vitro cytotoxicity potential using the standard MTT (3-(4,5-dimethylthiazol- 2-yl)-2,5- diphenyltetrazolium bromide) assay against a panel of three human cancer cell lines: Lung carcinoma A-549, Colon carcinoma HT-29, and Breast Cancer MDA MB-231. All the compounds were subjected to in vitro antibacterial activity against Bacillus subtilus (ATCC 6633), Staphylococcus aureus (ATCC-25923), Escherichia coli (ATCC-25922), and Pseudomonas aeruginosa (ATCC- 27853) and their minimal inhibitory concentrations were determined. © Springer Science+Business Media, LLC 2010.


Sirisha K.,Kakatiya University | Shekhar M.C.,Indian National Institute of Pharmaceutical Education and Research | Umasankar K.,Medicinal Chemistry Research Division | Mahendar P.,Kakatiya University | And 3 more authors.
Bioorganic and Medicinal Chemistry | Year: 2011

The overexpression of multidrug resistance protein 1 (MRP1) by tumor cells results in multidrug resistance (MDR) to structurally unrelated anticancer drugs. Circumvention of MDR by combination of chemosensitizers with antitumor compounds is a new field of investigation in cancer chemotherapy. Much effort has been put-in recently to identify the modulators/inhibitors of MRP1 to overcome the MDR. 1,4-Dihydropyridine (DHP) derivatives are indicated to be a new class of MRP1 inhibitors in cancer treatment. Molecular docking studies were carried out on 48 newly synthesized DHP derivatives with the crystal structure of MRP1 to gain some structural insights on the binding mode and possible interactions with the active site of MRP1 (NBD1). The 10 top-ranked molecules were selectively evaluated, experimentally for their MRP1 inhibitory effect using the insect cell membrane MRP1 ATPase assay. The inhibitory capacity (IC50 concentrations) of the test compounds was compared with the reported IC50- or the Ki-concentrations for benzbromarone, a standard MRP1 inhibitor. Amongst the compounds tested, compounds IA 1 and IIA5 were found to exhibit a potent MRP1 inhibitory action with IC50 values of 20 ± 4 and 14 ± 2 μM (mean ± SD), respectively as compared to benzbromarone (IC50 = 4 μM). The compound IIA5, in particular was found to be more potent than IA1 in accordance with the docking results. These new DHP derivatives possess promising characteristics for their development as MDR reversal agents. © 2011 Elsevier Ltd. All rights reserved.


Mahendar P.,Kakatiya University | Sirisha K.,Medicinal Chemistry Research Division | Kulandaivelu U.,Medicinal Chemistry Research Division | Shankar P.L.J.,Alpha Arts and Science College | And 2 more authors.
Journal of Molecular Modeling | Year: 2012

The activation of telomerase represents an early step in carcinogenesis. Increased telomerase expression in malignant tumors suggests that telomerase inactivation may represent a potential chemotherapeutic target. In this work, existing anticancer drugs were docked against telomerase reverse transcriptase (TERT) using a Lamarckian genetic algorithm (LGA). Autodock's scoring function was applied to each of the molecules in order to identify the inhibitor with the strongest pharmacological action. The structural insights provided by this study regarding binding poses and possible interactions, free energies of binding, and drug scores aided in the identification of potential inhibitory compounds. The ranks of the various ligands investigated were based on the final docked energy values. Among nine selected compounds, vindesine, temsirolimus, and cyclosporine were found to be more potent TERT inhibitors than the standard inhibitor, curcumin. © Springer-Verlag 2012.


Karuppasamy M.,Birla Institute of Technology | Mahapatra M.,Birla Institute of Technology | Yabanoglu S.,Hacettepe University | Ucar G.,Hacettepe University | And 6 more authors.
Bioorganic and Medicinal Chemistry | Year: 2010

3,5-Diaryl pyrazolines analogs were synthesized and evaluated for their monoamine oxidase (MAO) inhibitory activity. The compounds were found reversible and selective towards MAO-A with selectivity index in the magnitude of 103-105. The docking studies were carried out to gain further structural insights of the binding mode and possible interactions with the active site of MAO-A. Interestingly, the theoretical (Ki) values obtained by molecular docking studies were in congruence with their experimental (Ki) values. © 2010 Elsevier Ltd. All rights reserved.


Sathish N.K.,Medicinal Chemistry Research Division | GopKumar P.,NITK | Rajendra Prasad V.V.S.,Medicinal Chemistry Research Division | Shanta Kumar S.M.,Medicinal Chemistry Research Division | Mayur Y.C.,Medicinal Chemistry Research Division
Medicinal Chemistry Research | Year: 2010

A series of new 1,3-dimethyl acridone derivatives were synthesized with different alkyl side chain (propyl and butyl) substitution at N 10-position and highly basic amine groups at terminal end of alkyl side chain. All the synthesized molecules were screened for their cytotoxic activity against human breast adenocarcinoma (MCF-7) and human promyelocytic leukemia (HL-60) cell lines. DNA binding constants (Ki) of selected compounds were determined with calf-thymus DNA. Results showed that the molecules 7, 8, 10, 11, 12, 13, 14, and 15 exhibited good cytotoxic activity with IC50 value <10 μM. Compound 14 having (β- hydroxyethyl) piperazine butyl side chain exhibited potent cytotoxic activity against MCF-7 cell line and DNA-intercalating properties. Examination of the relationship between lipophilicity and acridone derivatives showed poor correlation. © Birkhäuser Boston 2009.


Sathish N.K.,Medicinal Chemistry Research Division | Mayur Y.C.,Medicinal Chemistry Research Division
Research Journal of Pharmaceutical, Biological and Chemical Sciences | Year: 2010

N-Alkylation of 1,3-disubstituted acridones has been done under microwave irradiation in absence of solvent. Various dimethyl and diacetoxy substituted acridones have been alkylated at N10-position with alkyl halides (1-bromo, 3-chloro propane and 1-bromo, 4-chloro butane) by using NaOH/K2CO3 adsorbed on Al2O3 in the presence of TBAB under microwave irradiation. The compound 3a with 1,3-dimethyl substitution, showed good yield.

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